NM_000372.5:c.820-5303C>A

Variant names:

• chr11-89185899-C-A
• rs3793976
• NM_000372.5:c.820-5303C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000372.5(TYR):​c.820-5303C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 152,036 control chromosomes in the GnomAD database, including 4,763 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (4763 hom., cov: 32)
• Consequence: TYR NM_000372.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.197
• Publications: 4 publications found

Genes affected

TYR (HGNC:12442): (tyrosinase) The enzyme encoded by this gene catalyzes the first 2 steps, and at least 1 subsequent step, in the conversion of tyrosine to melanin. The enzyme has both tyrosine hydroxylase and dopa oxidase catalytic activities, and requires copper for function. Mutations in this gene result in oculocutaneous albinism, and nonpathologic polymorphisms result in skin pigmentation variation. The human genome contains a pseudogene similar to the 3' half of this gene. [provided by RefSeq, Oct 2008]

TYR Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• oculocutaneous albinism type 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Waardenburg syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• minimal pigment oculocutaneous albinism type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• oculocutaneous albinism type 1B

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• temperature-sensitive oculocutaneous albinism type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYR	NM_000372.5	c.820-5303C>A		intron_variant	Intron 1 of 4	ENST00000263321.6	NP_000363.1
TYR	XM_011542970.3	c.820-5303C>A		intron_variant	Intron 1 of 5		XP_011541272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYR	ENST00000263321.6	c.820-5303C>A		intron_variant	Intron 1 of 4	1	NM_000372.5	ENSP00000263321.4
TYR	ENST00000526139.1	n.881-5303C>A		intron_variant	Intron 1 of 2	1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31301 AN: 151920 Hom.: 4734 Cov.: 32

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.205

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.206 AC: 31389 AN: 152036 Hom.: 4763 Cov.: 32 AF XY: 0.206 AC XY: 15331 AN XY: 74316

African (AFR) AF: 0.434 AC: 17987 AN: 41414

American (AMR) AF: 0.160 AC: 2436 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 445 AN: 3470

East Asian (EAS) AF: 0.121 AC: 626 AN: 5174

South Asian (SAS) AF: 0.164 AC: 795 AN: 4834

European-Finnish (FIN) AF: 0.163 AC: 1725 AN: 10562

Middle Eastern (MID) AF: 0.164 AC: 48 AN: 292

European-Non Finnish (NFE) AF: 0.100 AC: 6818 AN: 68000

Other (OTH) AF: 0.210 AC: 443 AN: 2106

Alfa AF: 0.162 Hom.: 453

Bravo AF: 0.216

Asia WGS AF: 0.183 AC: 635 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.88
DANN	Benign	0.33
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3793976; hg19: chr11-88919067;